Loss of bone mass (osteopenia or osteoporosis) and accelerated loss of calcium from bone are major causes of medical illness. Increased bone resorption is commonly associated with many different diseases. These problems affect millions of persons in the U.S. alone. Examples of disorders due to increased bone resorption include: (a) Osteoporosis (loss of bone mass)--a major source of morbidity producing hip and vertebral fractures in elderly, post-menopausal women; (b) hypercalcemia (increased blood calcium concentrations)--a problem which occurs frequently in patients with hyperparathyroidism or cancer which can produce kidney failure, coma and death if not treated; (c) bone metastasis (spread of cancer cells into bone). In the absence of effective antitumor therapy (and this problem frequently afflicts persons who have proved resistant to anticancer therapy), cancer cells progressively erode the bone causing fractures and extreme pain. Clearly, a drug which could directly strengthen bone tissue and decrease bone resorption would be highly desirable.
A variety of treatments have been utilized to treat these various disorders (e.g. fluorides and estrogens for osteoporosis; intravenous fluids, diuretics, phosphates, and mithramycin for hypercalcemia; radiation treatments for bone metastases if the disease is not extensive). Each of these treatments suffers from certain disadvantages such as excessive toxicity, production of disordered bone growth, or weak activity.
Accordingly, a search has been undertaken to discover agents which inhibit calcium resorption from bone.
Gallium is a metal which belongs to the Group IIIa elements of the periodic table. By mechanisms which are still uncertain, radioactive gallium salts are known to accumulate in certain tumors (Dudley H. C. et al, Radiology, 50: 571, (1950). 67-Gallium citrate is currently used for diagnostic purposes in patients with bone infections and malignant diseases (McCaffrey J. A. et al, AM J Med 60: 523, 1976; Hoffer, P, J Nuc Med 21: 394, (1980)). In 1952, King et al (Arch. Int. Med. 90:785 (1952)) first showed that injections of highly radioactive gallium caused tumor regression in cancer patients. Non-radioactive salts of gallium and other Group IIIa metals were first evaluated for their anticancer activity in 1971 (Hart, M. M., Adamson R. H. et al, Proc Nat Acad Sci (USA) 68:1623, 1971; Hart, M. M., Smith C. F., et al, J Nat Cancer Inst 47:1121, (1971)). Gallium was found to be the most potent and least toxic element for reducing the size of animal tumors. The anionic component (i.e. whether the salt was a nitrate or a chloride) made no significant difference with respect to the direct anticancer action (Adamson, R. H. et al, Cancer Chemother Rep 59:599, (1975)). After completing preclinical toxicologic studies, gallium nitrate entered into clinical trials as a cytotoxic anticancer agent in 1976. U.S. Pat. No. 4,303,636 discloses a method of cancer treatment which uses radioactive 67-gallium, as a cytotoxic agent.
It is the use of gallium as an inhibitor of calcium resorption from bone that is the subject of the present invention.